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Gene Therapy of Cystic Fibrosis Full Members

Name: Richard C. Ahrens, MD

Title: Professor

Focus Area: Dr. Ahrens is Co-Director of the CF Clinical Center. He has significant clinical research experience in the evaluation of pharmacologic treatment for CF lung disease, as well as in the clinical care of CF patients. His primary interests are: 1) the development of novel study designs to meet challenges in the pharmacologic management of CF pulmonary disease, and 2) the in vivo and in vitro assessment of aerosol drug delivery to the lung.

Focus Area: Dr. Apicella’s laboratory studies bacterial pathogenesis of Haemophilus influenzae, a bacteria most commonly detected in the lower airway of CF patients during early-stage disease. The majority of the work has focused on the role of surface glycolipids in pathogenesis, biofilm formation, quorum sensing, and survival within airway epithelial cells. His laboratory has demonstrated the role of the lipooligosaccharide structures in mimicry of human antigens, their role in co-opting epithelial cell receptors to allow entry into epithelial cells, and the introduction of sialic acid into their structure as a molecular mask to enable the bacteria to evade host innate defenses.

Focus Area: Dr. Banfi’s laboratory studies the role of Nox/Duox enzymes in lung innate immunity and how CFTR dysfunction inhibits antibacterial activity at the airway surface. This reactive oxygen-mediated innate immune system involves DUOX-mediated H2O2 production at the airway surface by airway epithelial cells, thiocyanate (SCN-) transport into the surface airway fluid through CFTR, and lactoperoxidase secretion into the airway surface fluid by submucosal glands. Currently, Dr. Banfi is using CF pigs and ferrets to explore both the therapeutic potential of small molecules (e.g., SCN-) to enhance the oxidative host defense in the CF airway and the pre-inflammatory abnormalities of the CF airway epithelium.

Focus Area: Dr. Durairaj’s research focuses on the prevention of airway infections and enhancing innate immunity, with most of her projects being translational in nature. Her current studies focus on the epidemiology of respiratory infections, the safety and efficacy of aerosolized xylitol in subjects with CF, and the safety of photodynamic therapy in newly intubated patients. Dr. Durairaj is PI of the Iowa Phase II Clinical Trials of Novel Therapies for CF (U01).

Focus Area: Dr. Engelhardt’s research includes: 1) study of the molecular and cellular pathogenesis of CF lung disease and CF-related diabetes, 2) development of novel larger animals models of CF, 3) the study of airway stem cell niches and submucosal gland development, and 4) development of gene therapies for CF and the biology of adeno-associated virus (AAV) infection. His laboratory is facile in the construction and use of many types of recombinant viral vectors (including adenovirus, AAV, lentivirus, and retrovirus). He also is PD/PI of a team science R24 that studies the pathogenesis of CF-related diabetes in CF ferrets and pigs, and includes a clinical trial in CF infants and children <5 yrs of age.

Focus Area: Dr. Fiegel has an established track record in the design and characterization of therapeutic aerosols. Her CF-related research includes: 1) the design of improved systems for drug/gene delivery to the lung, and 2) dissection of chemical and physical mechanisms that limit antibiotic delivery to P. aeruginosa biofilms at the airway surface. Her laboratory has also developed novel methods of imaging and quantifying P. aeruginosa biofilms and S. aureus biofilms grown on polarized human airway epithelia.

Focus Area: Dr. Gibson-Corley has nearly 10 years of experience in comparative pathology and translational research on animal models of human disease. She was recently recruited to UI to direct the Comparative Pathology Laboratory in the Department of Pathology. As director of the P30 Comparative Pathology Core, she will be integrated into many projects involving the CF pigs and ferrets.

Focus Area: Dr. Hoffman’s research is driven by questions pertaining to lung physiology, and by the development of imaging software and equipment designed specifically for the study of these questions. His research is applying single and multi-spectral multidetector row spiral CT imaging methodology to objectively follow human lung pathology and pathophysiology, with a particular emphasis on inflammatory lung diseases. His expertise has been very helpful for evaluating lung pathology and clearance in the CF animal models.

Focus Area: Dr. Keshavjee is a world-leading surgeon, scientist, and researcher in lung transplantation at Toronto, Canada. Since the Center was funded in 1998 he has: co-authored 11 manuscripts with its Members at UI; used the Vector Core for his gene therapy work, which is geared to reducing inflammation in the transplanted lung; and has continuously played a critical role in the Center’s CF Lung Tissue Acquisition Program. Moving forward, Dr. Keshavjee’s continued membership will also enhance the growing program on pathophysiology of bronchiolitis obliterans by Drs. Parekh and Eberlein.

Focus Area: Dr. McNamara’s research is primarily focused on the development of nucleic acid-based approaches for diagnosing infectious diseases. In collaboration with Center Member Dr. Alex Horswill, he has develop a diagnostic imaging approach for S. aureus infections based on chemically modified oligonucleotide probes that are specifically activated by micrococcal nuclease (see Hernandez et al., Nature Medicine, 2014). Further preclinical development of this approach in CF pigs and ferrets is ongoing.

Focus Area: Dr. Meyerholz serves as Director of the Division of Comparative Pathology in the Department of Pathology. His research efforts are devoted mainly to the study of CF in pig and ferret models. While he plays a significant role in bridging pathology with molecular mechanisms of disease in CF pig and ferret models, he also is responsible for independent scholarly work in these models.

Focus Area: Dr. McCray has a long-standing interest in CF, epithelial biology, genomics, innate immunity, and the application of gene transfer to CF lung disease. He is an expert in mucosal immunity and antimicrobial proteins. Dr. McCray has longstanding collaborations with Drs. Engelhardt, Sinn, Stoltz, Welsh, and Zabner. His research on FIV lentiviral vector systems led to the development of new pseudotypes that enhance airway epithelial cell transduction in CF ferrets and pigs. His research has also uncovered miRNA networks that regulate CFTR processing at the level of the endoplasmic reticulum and can be used to enhance deltaF508-CFTR processing to the plasma membrane. Dr. McCray directs a PPG focused on CF gene therapy.

Focus Area: Dr. Larson Ode was recruited to UI three years ago to establish a CFRD presence and clinic. Since then she has been highly engaged in the ferret and pig CFRD research programs at UI. For example, she initiated a clinical trial studying oral glucose tolerance and insular/entero-insular hormonal abnormalities in CF children 3 months to 5 years of age, based on data from the CF ferrets. She directs this clinical trial at UI, and collaborates with Dr. Moran at the University of Minnesota on this project.

Focus Area: Dr. Norris has broad expertise in the integrative physiology of diabetes. His laboratory studies the early pathogenesis of cystic fibrosis related diabetes (CFRD) in ferret and pig models, with a focus on redox stress, lipid abnormalities, and metabolic disease contributions to altered islet function in CFRD. Dr. Norris brings substantial expertise to the Center in the study of CFRD pathogenesis. He is PI on an R01 and an R24 that are solely focused on CFRD research, and is co-I on the CFRD clinical trial at UI.

Focus Area: Dr. Ostedgaard has a long-standing track record in the biology and biochemistry of CF disease processes, with a historical focus on structure/function of CFTR and the creation of functional CFTR minigenes for rAAV-directed gene therapy. More recently, she has been working to understand the molecular basis of mucin abnormalities in CF pigs, and their link to infection and inflammation.

Focus Area: Dr. Reinhardt’s research focuses on using imaging and image analysis to study normal lung function, and to detect variations indicative of early disease. Using CT imaging and image registration, he has developed a set of textural and biomechanical features and machine learning to characterize lung disease involving CF, COPD, emphysema, and fibrosis. He collaborates with members of the Center in applying these technologies to the study of lung disease in the CF pig and ferret models.

Focus Area: Dr. Rice is a leader in developing targeted DNA delivery systems, with unique expertise in the incorporation of PEGylated polyacridine peptides for cell targeting that have enhanced stability in the blood and reduced phagocytic clearance. His R01 focuses on developing DNA complexes that target somatostatin receptor-expressing cells in the periphery. As this receptor is expressed on beta-cells, alpha-cells, and exocrine acinar cells of the pancreas, it represents unique opportunities for gene therapy of CFRD in the CF ferret and pig models. He has also developed mannose-targeted polyplexes, for targeting macrophages in the CF ferret lung.

Focus Area: Dr. Sinn's research focuses on the development of integrating vector systems for the treatment of CF lung disease. His independent R01- and CFF-funded research is focused on developing a piggyBac hybrid vector system that integrates into airway epithelial cells, and engineering transposases and zinc-fingers to integrate transgenes into safe-harbor genomic loci. These systems, in addition to novel lentiviral pseudotypes developed by Dr. Sinn, are being used for lung-directed gene therapy in the CF pig and ferret models. In particular, he developed a recombinant FIV-GP64 vector that his highly tropic for the newborn ferret airways.

Focus Area: Dr. Starner is Director of the CF Clinical Center at UI, and will serve as Director of the Clinical Core of this P30. His lab performs basic, translational, and clinical research with emphasis on the early pathophysiology of CF lung disease. His basic research focused on innate immunity and interactions between airway epithelia and bacteria, predominantly Haemophilus influenzae. His translational projects include validating lung clearance index as a new measure of early lung disease.

Focus Area: Dr. Stoltz has played a major role in various aspects of development of the CF pig models, including development of the surgical correction of the meconium ileus phenotype and more recently the generation of gut-corrected CF pigs. His areas of research include the role of CFTR in airway development and CF disease pathogenesis involving goblet cell functions in innate immunity and inflammation. He received an NIH Director’s New Innovator Award to investigate goblet cell and mucus biology, based on conditionally ablating airway goblet cells using the thymidine kinase system in transgenic wild-type and CF pigs.

Focus Area: Dr. Thorne's research expertise includes the development of aerosal-based techniques for delivering therapeutic agents and gene therapy vectors to the lung, as well as studies of innate immune responses to inhaled biological materials (such as LPS). His group collaborates extensively to provide acute, subchronic and chronic inhalation models with rigidly controlled generation of aerosols and vapors to replicate human exposures to environmental agents or therapeutic interventions delivered to the lung of CF models.

Focus Area: Dr. Welsh has a long-standing interest in the study and treatment of CF. His laboratory is using a multi-faceted approach to understand the biology of cystic fibrosis, with several areas of emphasis. The first is an investigation of the structure and function of CFTR. The second is an exploration of how CFTR defects lead to impaired airway innate immunity and lung disease. To aid this research, he has generated a number of porcine CF models (KO, deltaF508-CFTR, gut-corrected KO, and inducible-CFTR) that provide exciting new opportunities to understand the CF disease process.

Focus Area: Dr. Wine has been a consortium Member of the Center since he held a P30 pilot grant in 2010. Interactions with Dr. Wine were driven by the creation of the new CF pig and ferret models, and the need to characterize submucosal gland defects in these models. His laboratory focuses on dissecting airway submucosal gland function and their involvement in the pathogenesis of CF lung disease. Recent collaborative efforts include study of the glandular secretome of non-CF and CF human, pigs and ferrets.

Focus Area: Dr. Yahr’s research program is primarily focused on the Pseudomonas aeruginosa type III secretion system, with the general aims of defining regulatory mechanisms that control T3SS gene expression and determining the role of the T3SS in pathogenesis. He has broad training in microbial genetics and physiology, protein biochemistry, protein transport systems, and microbial pathogenesis. He collaborates with Drs. Horswill, Zabner, Klesney-Tait, and Stoltz, and we expect his collaborations to grow in the Center.

Focus Area: Dr. Yan's research pertains to the molecular biology of rAAV and HBoV1, and to their development as recombinant viral vectors for use in gene therapy of CF lung disease. He recently developed a novel chimeric parvoviral vector (rAAV2/HBoV1) that is capable of packaging the full-length CFTR cDNA with a strong promoter of 850 bp. The HBoV1 capsid transduces the apical membrane of human airway epithelia with remarkable efficiency and has a packaging capacity 18% larger than that of AAV. Dr. Yan also collaborates with Drs. McCray and Sinn in testing FIV and PiggyBac transposon vectors in the CF ferret model.

Focus Area: Dr. Zabner has significant experience in basic CF research, clinical CF research, and the care of patients with CF. His research elegantly bridges studies in CF patients with those in CF animal models. For example, his research in the CF pig model linking reduced bicarbonate and pH to reduced bacterial killing (Nature 2012) prompted studies in CF patients and confirmed this finding in infants. His main research interests include: 1) elucidating antimicrobial mechanisms in the airway surface liquid, 2) developing vectors for gene therapy in CF, and 3) investigating the endogenous airway lactonase ‘paraoxonase’, which can degrade quorum-sensing molecules used by Pseudomonas Aeruginosa.

Focus Area: Dr. Zavazava’s research focuses on induced pluripotent stem (iPS) cells and methods for differentiating them into specific lineage-committed cells. A major focus of his research is generating iPS-derived beta-cells for cell therapy applications in diabetes. Given the increasing focus of the Center on CFRD, Dr. Zavazava’s membership provides unique opportunities for collaboration in the CF pig and ferret models. Initially, he plans to generate iPS cells from CF ferrets and to develop methods for directing their differentiation toward endocrine and exocrine lineages in the pancreas.